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PubMed1982

[Analysis of lymphocyte adhesion and the phenomenon of immunologic adhesion inhibition].

Investigations were performed in rabbits to elucidate the cell physiological parameters of the inhibitor reaction of adhesion. For this purpose, an improved method of measuring the cell adhesion was used. The well-known fact that culture cells will reveal a much stronger reaction could be confirmed. This may be due to the high increase of T-lymphocytes because of findings concerning cell differentiation with acid alpha-naphthylacetate esterase (ANAE), whereas no corresponding results could be found for the particular role of macrophages. It could be proved that the inhibitor reaction already began 20 minutes after the antigen contact. On the basis of these facts beta-lymphotoxin might be assumed to play a part in the inhibitor reaction. A direct relationship between oxygen consumption and the inhibitor reaction of adhesion could not be proved. The respiratory depression frequently observed might be due to the cytotoxic effect of excreted lymphotoxins. As the inhibitor reaction of adhesion could be identified even after 1-1 1/2 years, it can be regarded as a longterm immunophenomenon. The findings with metabolic blockers underline that the primary adhesion of lymphocytes is supported by the oxidative metabolism and not by glycolysis which is generally characteristic of granulocytes.

Animals↗
PubMed1997

Prevention of adhesions by Seprafilm, an absorbable adhesion barrier: an incisional hernia model in rats.

Adhesion formation, which is almost inevitable following incisional hernia repair with prosthetic mesh, may lead to intestinal obstruction and enterocutaneous fistulae. Physical barriers, namely carboxymethylcellulose and hyaluronic acid, have been reported to lessen the intra-abdominal adhesions. To evaluate the effects of Seprafilm (Genzyme Corp., Cambridge, MA), a bioresorbable, translucent membrane composed of carboxymethylcellulose and hyaluronic acid, in the presence of a foreign body such as polypropylene mesh, an incisional hernia model in rats was used. Twenty-four male rats were divided into two groups: control (12) and Seprafilm (12). A defect, measuring 1.5 x 2.5 cm, was created in each animal. Control animals had the polypropylene mesh sutured to the defect, whereas in the other group, two membranes of Seprafilm were laid over the abdominal viscera before repair with polypropylene mesh. Half of the animals from each group were killed at postoperative day 7 and remaining half at day 30 for adhesion scoring and histological evaluation of wound healing. Seprafilm animals had fewer adhesions compared with control animals (P = 0.0008). Seprafilm had no adverse effect on wound healing. This membrane seems to have the potential to lessen the adhesion-related morbidity following incisional hernia repair.

Animals↗
PubMed1997

Spleen-derived stromal cells. Adhesion molecules expression and lymphocyte adhesion to reticular cells.

The final steps of lymphocyte differentiation occur in secondary lymphoid organs where B and T lymphocytes interact with the lymphoid microenvironment. Although numerous studies describe the interactions of murine lymphocytes with dendritic, follicular and other antigen presenting cells, little is known on the interactions between lymphocytes and reticular cells, an important cellular component of spleen stroma. In this work we describe the culturing of complete murine spleen stromas and of two cell lines, Sp-1 and Sp-2, identified as of possible reticular origin, and describe the adhesive interactions between murine lymphocytes and human lymphoid cells with murine spleen stromal cells. FACS analysis indicates that the Sp-1 cell line shows a single cell type expressing VCAM-1 and CD44 constitutively. They do not express any of the markers described for follicular cells, interdigitating cells, macrophages or endothelial cells. Our data suggests that these cells represent a population of spleen reticular cells. The Sp-2 cell line shows two phenotypically different cell types that grow in association. FACS analysis demonstrates that both cell types express VCAM-1 and CD44 constitutively, but that they can be differentiated by the expression of CD11b and FcR. These data suggest that the Sp-2 cell line is composed of one type of stromal cell growing over an adherent layer of reticular cells. Furthermore, analysis of the non-B non-T cell fraction prepared from murine spleen shows that approximately 30% of these cells correspond to the CD44/VCAM-1 double positive cells. Murine B and T cells adhere to the complete stromas and to Sp-1 and Sp-2 cell lines. Activation of B cells with LPS had no effect on binding while binding of T cells to complete stromas increased up to threefold after Con-A treatment. Adhesion of human lymphoblastoid Daudi cells to complete spleen stromas is blocked by an anti-(murine) VCAM-1 antibody but not by an antibody to the (human) integrin alpha 4 subunit, while adhesion to the Sp-1 and Sp-2 stromas is blocked by antibodies against both molecules. Also, adhesion of Ramos cells to Sp-2 stromas is inhibited by antibodies to the integrin alpha 4 subunit and to murine VCAM-1. Antibodies to other adhesion receptors such as the integrin beta 2 subunit, ICAM-1 or CD44 have no effect on human cell binding to these stromas. Our results suggest that we have isolated a fraction of splenic reticular cells and that these cells can be cultured as a distinct cell line. The finding that these cells express CD44 and VCAM-1 constitutively and use some of these molecules for lymphocyte binding suggests that spleen reticular cells may be involved in the regulation of normal lymphocyte traffic through the spleen.

Animals↗
PubMed1996

Focal adhesion kinase pp125FAK is associated with both intercellular junctions and matrix adhesion sites in vivo.

Previous studies have characterized pp125FAK as a focal adhesion (FA)-associated non-receptor tyrosine kinase. However, there are few data available on the expression and localization of this kinase in tissues. In this study we show that in human tissues the highest expression of pp125FAK is found in some developing epithelia, where pp125FAK is associated with either intercellular junctions or with sites of adhesion to the basement membrane, whereas the same adult tissues show only a faint reactivity. Connective tissue cells do not show any reactivity for pp125FAK in vivo, but developing arterial smooth muscle expresses pp125FAK at high levels. The expression pattern in malignant tissues is variable, but most carcinomas do not express this kinase. In primary cultures of human amnion epithelial cells pp125FAK first becomes associated with the polarized adhesion lamellae, but is subsequently translocated to the forming adherens junctions (AJs). Later upon culturing pp125FAK becomes associated with prominent FAs, as in cultured cell lines. Taken together, our results suggest that the association of pp125FAK with FAs in cultured cells is principally due to a process of adaptation, whereas in vivo pp125FAK mainly functions as a regulatory component of intercellular AJs and cell-matrix adhesions of developing epithelia and also in developing arterial smooth muscle.

Adult↗
PubMed1993

Effect of dexamethasone, 6-mercaptopurine and cyclosporine A on intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression.

The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) is increased in immune-mediated diseases. These adhesion molecules promote the adherence of inflammatory cells to parenchymal target cells. We have examined the effect of immunosuppressants on the expression of ICAM-1 and VCAM-1 in a renal tubular epithelial cell line. We found that dexamethasone (4-40 micrograms/mL), the azathioprine metabolite 6-mercaptopurine (10-100 micrograms/mL) and cyclosporine A (0.1-1 microgram/mL) have no effect on the basal and the tumor necrosis factor-alpha- or interleukin-1-stimulated expression of these adhesion molecules. We conclude that these immunosuppressants do not directly influence the expression of ICAM-1 and VCAM-1 by renal tubular epithelium.

Animals↗
PubMed1995

Adhesion molecule expression and lymphocyte adhesion to cerebral endothelium: effects of measles virus and herpes simplex 1 virus.

Expression of endothelial cell (EC) adhesion molecules is increased in inflammatory neurological disorders and this may regulate lymphocyte homing to the central nervous system (CNS). Viral encephalitis is characterised by lymphocytic infiltration of the CNS and one mechanism of this response may be EC adhesion molecule induction with consequent inflammatory cell/EC binding. This report characterises the effects of herpes simplex 1 (HSV1) or measles virus (MV) infection of BALB/c brain microvascular EC in vitro on adhesion of naive syngenic splenocytes and levels of ICAM-1. Adhesion was enhanced by 42% for MV-infected cells and by 73% for HSV-1-infected EC. At the multiplicities of infection employed, levels of ICAM-1 were upregulated on HSV-1-infected EC, but not on MV-infected EC. It is concluded that ICAM-1/ligand interactions do not play a role in mediation of MV enhancement of adherence, but represent one mechanism responsible for increased lymphocyte adherence to HSV-1-infected cerebral EC.

Animals↗
PubMed2006

The regulation of integrin-mediated osteoblast focal adhesion and focal adhesion kinase expression by nanoscale topography.

An important consideration in developing physical biomimetic cell-stimulating cues is that the in vivo extracellular milieu includes nanoscale topographic interfaces. We investigated nanoscale topography regulation of cell functions using human fetal osteoblastic (hFOB) cell culture on poly(l-lactic acid) and polystyrene (50/50 w/w) demixed nanoscale pit textures (14, 29, and 45nm deep pits). Secondary ion mass spectroscopy revealed that these nanotopographic surfaces had similar surface chemistries to that of pure PLLA because of PLLA component surface segregation during spin casting. We observed that 14 and 29nm deep pit surfaces increased hFOB cell attachment, spreading, selective integrin subunit expression (e.g., alphav relative to alpha5, beta1, or beta3), focal adhesive paxillin protein synthesis and paxillin colocalization with cytoskeletal actin stress fibers, and focal adhesion kinase (FAK) and phosphorylated FAK (pY397) expression to a greater degree than did 45nm deep pits or flat PLLA surfaces. Considering the important role of integrin-mediated focal adhesion and intracellular signaling in anchorage-dependent cell function, our results suggest a mechanism by which nanostructured physical signals regulate cell function. Modulation of integrin-mediated focal adhesion and related cell signaling by altering nanoscale substrate topography will have powerful applications in biomaterials science and tissue engineering.

Biocompatible Materials↗
PubMed1996

Platelet endothelial cell adhesion molecule-1 (PECAM-1) homophilic adhesion is mediated by immunoglobulin-like domains 1 and 2 and depends on the cytoplasmic domain and the level of surface expression.

PECAM-1/CD31 is vascular cell adhesion and signaling molecule of the Ig superfamily that plays a role in neutrophil recruitment at inflammatory sites and may be involved the release of leukocytes from the bone marrow and in cardiovascular development. The interactions of PECAM-1 with its ligands are complex in that it is able to bind both with itself (homophilic adhesion) or with non-PECAM-1 ligands (heterophilic adhesion). Although the factors that regulate ligand binding are not fully understood, these interactions are regulated in part by its large cytoplasmic domain, a region of 118 amino acids encoded by 8 exons of its gene (exons 9-16). The purpose of this work was to better define the mechanisms of PECAM-1-dependent homophilic adhesion by analyzing the binding interactions of L-cells expressing full-length and selectively mutated forms of human, murine, and human/murine chimeric PECAM-1 molecules in an established aggregation assay. These studies demonstrate that 1) the minimal length of the cytoplasmic domain required for cellular aggregation is represented within the sequences encoded by exons 9 and 10, 2) removal or addition of the sequences encoded by exon 14 from the cytoplasmic domain can determine whether the mechanism of aggregation is a heterophilic calcium-dependent process or a homophilic calcium-independent process, 3) high levels of surface expression of PECAM-1 on the cell surface change the mechanism of aggregation from heterophilic to homophilic, and 4) PECAM-1-dependent homophilic binding appears to involve the direct interaction of only the first two extracellular Ig-like domains. These data suggest that PECAM-1-ligand interactions can be regulated through multiple pathways including alterations of the cytoplasmic domain and the level of surface expression.

Animals↗
PubMed1992

Lymphocyte adhesion through very late antigen 4: evidence for a novel binding site in the alternatively spliced domain of vascular cell adhesion molecule 1 and an additional alpha 4 integrin counter-receptor on stimulated endothelium.

Recent studies demonstrate that alternative splicing of mRNA from a single gene can produce two forms of vascular cell adhesion molecule 1 (VCAM-1): a six-immunoglobulin (Ig) domain form (VCAM-6D) and a seven-Ig domain form (VCAM-7D). Using a COS cell transient expression assay, we investigated whether VCAM-6D and VCAM-7D differ functionally in adhesion to the integrin VLA-4 (CD49d/CD29) on lymphoid cells. Binding of lymphoid cell lines and peripheral blood lymphocytes was completely blocked by VLA-4 monoclonal antibody (mAb) and one VCAM-1 mAb (4B9) to both VCAM-6D and VCAM-7D, whereas one VCAM-1 mAb (E1/6) completely blocked binding to VCAM-6D but only partially inhibited binding to VCAM-7D. We conclude that there is one VLA-4 binding site in the six Ig domains shared between VCAM-6D and VCAM-7D, and that the alternatively spliced domain 4 present in VCAM-7D provides a second VLA-4 binding site that is blocked by 4B9 but not the E1/6 mAb. We compared the inhibitory effects of anti-VCAM-1 and anti-VLA-4 mAbs on lymphoid cell adhesion to cultured human umbilical vein endothelial cells (HUVEC). The anti-VCAM-1 mAb 4B9 blocked the binding of PBL and lymphoid tumor cells to stimulated HUVEC better than the anti-VCAM-1 mAb E1/6. Because VCAM-7D is the predominant form of VCAM-1 expressed by stimulated endothelial cells, this difference in VCAM-1 mAb inhibition is attributed to lymphoid cell binding to VCAM-7D on stimulated HUVEC. Although the anti-VLA-4 mAb and anti-VCAM-1 mAb 4B9 equally inhibited PBL binding to stimulated HUVEC, mAb 4B9 inhibited the binding of two lymphoid cell lines significantly less than anti-VLA-4 mAb. Combination of 4B9 mAb with function-blocking antiserum to human fibronectin, a second known ligand for VLA-4, also failed to inhibit as much as anti-VLA-4 mAb. These findings suggest that adhesion of lymphoid cell lines through VLA-4 or other alpha 4 integrins may involve inducible counter-receptor(s) on endothelium distinct from either VCAM-1 or fibronectin. Time course experiments indicate that the fraction of alpha 4 integrin-dependent binding that can be blocked by anti-VCAM-1 mAb E1/6 rises and peaks within 2 h of tumor necrosis factor (TNF) stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and homing factor CD44 after engraftment of Graves' lymphocytes in xenotransplanted human thyroid tissue in athymic nude mice.

The expression of adhesion molecules on thyrocytes and endothelium cells plays an important role in the pathogenesis of Graves' disease (GD). The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1), and the homing receptor CD44 are responsible for the specific migration of lymphocytes in autoimmune thyroid diseases (AITD) (homing). Eight weeks after transplantation of thyroid tissue from 26 patients with nonautoimmune thyroid disease (nontoxic nodular goiter [NTG]) into nude mice, peripheral (PBL) and intrathyroidal lymphocytes (ITL) from 14 patients with NTG and 12 patients with GD were grafted into the animals. Two days after lymphocyte engraftment, the thyroid transplants were examined histologically (HE) and immunohistologically stained with monoclonal antibodies directed against ICAM-1, VCAM-1, and CD44. After injection of GD lymphocytes, thyroid transplants expressed significantly more ICAM-1, VCAM-1, and CD44 than after injection of NTG lymphocytes. This expression was even more pronounced after grafting of GD intrathyroidal lymphocytes. Our data demonstrate that only GD lymphocytes induce the expression of adhesion molecules and homing factor CD44, both of which play an important role in the migration of lymphocytes and induction of the autoimmune process.

Animals↗
PubMed2002

The association of ASAP1, an ADP ribosylation factor-GTPase activating protein, with focal adhesion kinase contributes to the process of focal adhesion assembly.

ASAP1 (ADP ribosylation factor [ARF]- GTPase-activating protein [GAP] containing SH3, ANK repeats, and PH domain) is a phospholipid-dependent ARF-GAP that binds to and is phosphorylated by pp60(Src). Using affinity chromatography and yeast two-hybrid interaction screens, we identified ASAP1 as a major binding partner of protein tyrosine kinase focal adhesion kinase (FAK). Glutathione S-transferase pull-down and coimmunoprecipitation assays showed the binding of ASAP1 to FAK is mediated by an interaction between the C-terminal SH3 domain of ASAP1 with the second proline-rich motif in the C-terminal region of FAK. Transient overexpression of wild-type ASAP1 significantly retarded the spreading of REF52 cells plated on fibronectin. In contrast, overexpression of a truncated variant of ASAP1 that failed to bind FAK or a catalytically inactive variant of ASAP1 lacking GAP activity resulted in a less pronounced inhibition of cell spreading. Transient overexpression of wild-type ASAP1 prevented the efficient organization of paxillin and FAK in focal adhesions during cell spreading, while failing to significantly alter vinculin localization and organization. We conclude from these studies that modulation of ARF activity by ASAP1 is important for the regulation of focal adhesion assembly and/or organization by influencing the mechanisms responsible for the recruitment and organization of selected focal adhesion proteins such as paxillin and FAK.

Animals↗
PubMed2005

Neutrophil migration across tight junctions is mediated by adhesive interactions between epithelial coxsackie and adenovirus receptor and a junctional adhesion molecule-like protein on neutrophils.

Neutrophil (polymorphonuclear leukocytes [PMN]) transepithelial migration during inflammatory episodes involves a complex series of adhesive interactions and signaling events. Previous studies have shown that key adhesive interactions between leukocyte CD11b/CD18 and basally expressed fucosylated glycoproteins followed by binding to desmosomal-associated JAM-C are key elements of the transmigration response. Here we provide the first evidence that PMN-expressed junctional adhesion molecule-like protein (JAML) regulates transmigration via binding interactions with epithelial coxsackie and adenovirus receptor (CAR). Experiments with a JAML fusion protein revealed specific binding of JAML to epithelial CAR expressed at tight junctions in T84 cell monolayers and normal human colonic mucosa. Furthermore, JAML-CAR binding is mediated via the membrane distal immunoglobulin (Ig) loop of CAR and the membrane proximal Ig loop of JAML. PMN bound to immobilized CAR but not JAML in a divalent cation-independent manner. Lastly, in assays of PMN transepithelial migration, JAML/CAR fusion proteins and their antibodies significantly inhibited transmigration in a specific manner. Taken together, these results indicate that JAML and CAR are a novel pair of adhesion molecules that play an important role in modulating PMN migration cross epithelial tight junctions. These findings add a new element to a multistep model of PMN transepithelial migration and may provide new targets for anti-inflammatory therapies.

Antibodies, Monoclonal↗
PubMed1998

Cytoplasmic tail regulates the intercellular adhesion function of the epithelial cell adhesion molecule.

Ep-CAM, an epithelium-specific cell-cell adhesion molecule (CAM) not structurally related to the major families of CAMs, contains a cytoplasmic domain of 26 amino acids. The chemical disruption of the actin microfilaments, but not of the microtubuli or intermediate filaments, affected the localization of Ep-CAM at the cell-cell boundaries, suggesting that the molecule interacts with the actin-based cytoskeleton. Mutated forms of Ep-CAM were generated with the cytoplasmic domain truncated at various lengths. All of the mutants were transported to the cell surface in the transfectants; however, the mutant lacking the complete cytoplasmic domain was not able to localize to the cell-cell boundaries, in contrast to mutants with partial deletions. Both the disruption of the actin microfilaments and a complete truncation of the cytoplasmic tail strongly affected the ability of Ep-CAM to mediate aggregation of L cells. The capability of direct aggregation was reduced for the partially truncated mutants but remained cytochalasin D sensitive. The tail truncation did not affect the ability of the transfectants to adhere to solid-phase-adsorbed Ep-CAM, suggesting that the ability to form stable adhesions and not the ligand specificity of the molecule was affected by the truncation. The formation of intercellular adhesions mediated by Ep-CAM induced a redistribution to the cell-cell boundaries of alpha-actinin, but not of vinculin, talin, filamin, spectrin, or catenins. Coprecipitation demonstrated direct association of Ep-CAM with alpha-actinin. Binding of alpha-actinin to purified mutated and wild-type Ep-CAMs and to peptides representing different domains of the cytoplasmic tail of Ep-CAM demonstrates two binding sites for alpha-actinin at positions 289 to 296 and 304 to 314 of the amino acid sequence. The results demonstrate that the cytoplasmic domain of Ep-CAM regulates the adhesion function of the molecule through interaction with the actin cytoskeleton via alpha-actinin.

Actinin↗
PubMed1994

Expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on proliferating vascular endothelial cells in diabetic epiretinal membranes.

The present study demonstrated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), the proliferating status of the neovascular endothelial cells, and the activation of vascular endothelial cells bearing the two cell adhesion molecules in diabetic epiretinal membranes by using double immunofluorescence and APAAP techniques. The results showed that ICAM-1 was detected in 36 out of 40 (90%) proliferative diabetic retinopathy epiretinal membranes, VCAM-1 was found in 32 out of 40 cases (80%); in 21 out of 26 (81%) vascularised membranes the endothelial cells of the new vessels in the membranes were still in a proliferative stage (positive for proliferating endothelial cell marker EN 7/44) and, further, in 20 out of 26 cases (77%) ICAM-1 was detected on the proliferating endothelial cells and VCAM-1 was found in 21 cases (81%). The expression of cell adhesion molecules, especially ICAM-1 and VCAM-1 in diabetic epiretinal membranes suggests that cell to cell interactions may play a significant role in the development of PDR membranes. In particular, the expression of ICAM-1 and VCAM-1 on proliferating endothelial cells indicates the activation of these cells, which is the first critical step for lymphocyte/endothelial cell interactions and the initiation of immune responses. The significance of proliferating status of the neovascularisation in the membranes may be related to the clinical course and prognosis of the disease.

Cell Adhesion Molecules↗
PubMed2002

Characterisation of adhesion receptors mediating lymphocyte adhesion to bronchial endothelium provides evidence for a distinct lung homing pathway.

BACKGROUND: The lung is an important tertiary lymphoid organ and many lung diseases are associated with disordered lung immunity. Unlike the gut (alpha4beta7 binding to MAdCAM-1) and skin (CLA+ve T cells binding to E-selectin) where the adhesion receptors involved in organ specific homing of T cells have been identified, the molecular pathways controlling lymphocyte migration to the lung are unclear. Using a modified version of the Stamper-Woodruff assay we have investigated the receptors mediating adhesion of peripheral blood lymphocytes to airway endothelium. METHODS: Longitudinal frozen sections of bronchus (8 micro m) obtained from lung resection specimens were incubated with T cell enriched peripheral blood mononuclear cells for 30 minutes under shaking conditions in the presence of a fluorescently labelled polyclonal anti-von Willebrand antibody to identify blood vessels. After fixation the percentage of blood vessels supporting adhesion was measured. Blocking monoclonal antibodies were used to determine the role of individual adhesion receptors in lymphocyte binding. RESULTS: Specific cation dependent binding of lymphocytes to bronchial endothelium was observed which was significantly inhibited by antibodies against P-selectin, PSGL-1, L-selectin, LFA-1, ICAM-1 and ICAM-2 but not E-selectin, VLA-4, VCAM-1 or Mac-1. This was consistent with the pattern of endothelial expression of these receptors with strong expression of P-selectin and ICAM-1, but negligible expression of E-selectin on bronchial endothelium. CONCLUSION: This study suggests an important role for PSGL-1/P-selectin in T cell migration into the bronchi and provides further evidence for a pattern of recirculation for respiratory tract homing T cells distinct from the gut and skin.

Bronchi↗
PubMed2002

A novel attribute of enoxaparin: inhibition of monocyte adhesion to endothelial cells by a mechanism involving cell adhesion molecules.

Enoxaparin is a low molecular weight heparin, widely accepted as anticoagulant or antithrombotic drug, and is likely to have a role in acute inflammation. To evaluate the anti-inflammatory potential of enoxaparin, we investigated the direct effect of the drug on the activation of endothelial cells. For this purpose we set up an in vitro system in which cultured valvular endothelial cells (VEC) activated by tumor necrosis factor alpha or lipopolysaccharide were exposed to a monocytic cell line; these conditions induced a significant adhesion of monocytes to VEC. Adhesion assays, ELISA, and flow cytometric analysis revealed that pretreatment with enoxaparin, at a relevant plasma concentration (16 microg/ml), acts upon activation of VEC by inhibition of lipopolysaccharide-induced E-selectin expression and tumor necrosis factor stimulated ICAM-1 expression, thus reducing monocyte adhesion to VEC. These results suggest a novel function of enoxaparin, namely to protect VEC from activation and inhibiting the expression of cell adhesion molecules.

Animals↗
PubMed2006

Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression.

OBJECTIVE: Tumor necrosis factor (TNF)-alpha initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-alpha-mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-alpha-responsive genes and functions. METHODS AND RESULTS: Human umbilical vein endothelial cells (ECs) were preincubated with inhibitors of PI3 kinase (LY294002), histone deacetylases (HDAC) (trichostatin A [TSA]), de novo protein synthesis (CHX), proteasome (MG-132), and GATA factors (K-11430) before exposure to TNF-alpha at 4 hours and analyzed by microarray. TNF-alpha-mediated induction of vascular cell adhesion molecule-1 (VCAM-1) was attenuated by all of these inhibitors, whereas in contrast, stimulation of intercellular adhesion molecule-1 (ICAM-1) was blocked by MG-132 alone. Moreover TSA blocked TNF-alpha-mediated induction of monocyte adhesion both in vitro and in vivo through the suppression of VCAM-1. Further analysis demonstrated that HDAC3 plays a significant role in the regulation of TNF-alpha-mediated VCAM-1 expression. CONCLUSIONS: TNF-alpha activates ECs via multiple signaling pathways, and these pathways may be selectively targeted to modulate EC function. Moreover, TSA treatment reduced monocyte adhesion via VCAM-1 suppression in vitro and in vivo, suggesting that TSA might be useful for the attenuation of the inflammatory response in EC.

Animals↗
PubMed1991

Thromboxane mediates diapedesis after ischemia by activation of neutrophil adhesion receptors interacting with basally expressed intercellular adhesion molecule-1.

Ischemic injury is characterized by neutrophil (PMN)--endothelial cell adhesion and diapedesis associated with thromboxane (TX) generation. Neutrophil-endothelial cell interaction is regulated in part by the leukocyte adhesion receptor CD 18 glycoprotein complex and the endothelial intercellular adhesion molecule-1 (ICAM-1). This study tests the role of TX in ischemia-induced diapedesis and evaluates whether the diapedesis is regulated by neutrophil or endothelial adhesion receptors. Plasma derived from rabbit hind limbs made ischemic for 3 hours (n = 6) and reperfused for 10 minutes had increased levels of TXB2 3,450 pg/ml, which was higher than sham rabbit (n = 6) values of 653 pg/ml (p less than 0.05). When introduced into abraded skin chambers placed on the dorsum of other normal rabbits (n = 6), this ischemic plasma induced 1,000 pg/ml of new TX synthesis and diapedesis of 1,235 PMN/mm3. The total TX concentration and PMN accumulations in blister fluid were correlated (r = 0.88, p less than 0.05). In contrast, sham rabbit plasma induced no TX synthesis and diapedesis of only 77 PMN/mm3 (p less than 0.05). Administration of 50 ng/ml of authentic TXB2 into blisters induced an accumulation of 453 PMN/mm3, which was higher than that in saline controls (18 PMN/mm3) (p less than 0.05). Pretreatment of normal rabbits used for the diapedesis assay (n = 4) with the TX synthetase inhibitor OKY 046 (2 mg/kg/hr) limited ischemic plasma and authentic TXB2 induced diapedesis to 142 and 76 PMN/mm3, respectively (both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗